Ribosomal Protein S7 Is Both a Regulator and a Substrate of MDM2

Summary MDM2associates with ribosomal proteinS7, and this interaction is required to inhibit MDM2's E3 ligase activity, leading to stabilization of MDM2and p53. Notably, the MDM2homolog MDMXfacilitates the inhibition of MDM2E3 ligase activity by S7. Further, ablation of S7 inhibits MDM2and p53 accumulation induced by different stress signals in some cell types. Thus, ribosomal/nucleolar stress is likely a key integrating event in DNA damage signaling to p53. Interestingly, S7 is itself a substrate for MDM2E3 ligase activity both in vitro and in vivo. An S7-ubiquitin fusion protein (S7-Ub) selectively inhibits MDM2degradation of p53 and is unaffected by MDMX. S7-Ub promotes apoptosis to a greater extent than S7 alone. This indicates that MDM2ubiquitination of S7 is involved in sustaining the p53 response. Thus, S7 functions as both effector and affector of MDM2to ensure a proper cellular response to different stress signals.